Cabozantinib in Advanced Renal Cell Carcinoma

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On April 25, 2016, a tablet formulation of cabozantinib (Cabometyx) was approved for treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy.1,2 The capsule formulation of cabozantinib (Cometriq) was previously approved for the treatment of metastatic medullary thyroid carcinoma.

Supporting Efficacy Data

The current approval was based on a phase III trial in which 653 patients with advanced renal cell carcinoma received cabozantinib at 60 mg daily (n = 331) or everolimus (Afinitor) at 10 mg daily (n = 322) until disease progression or unacceptable toxicity.2,3 Patients in both groups who had disease progression could continue treatment at an investigator’s discretion. The primary endpoint was progression-free survival on independent review among the first 375 randomly assigned patients.

Overall, patients had a median age of 62 years; 75% were male; 69% had received one prior antiangiogenic therapy; Memorial Sloan Kettering Cancer Center risk group was favorable for 46%, intermediate for 42%, and poor for 13%; and 54% had at least three organs with metastatic disease, including lungs (63%), lymph nodes (62%), liver (29%), and bone (22%).

The recommended daily dose of cabozantinib is 60 mg without food. The starting dose should be reduced to 40 mg once daily in patients with mild or moderate hepatic impairment; cabozantinib is not recommended for use in patients with severe hepatic impairment.

Cabozantinib in Kidney Cancer

Cabozantinib (Cabometyx) was approved for treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy.

The recommended daily dose of cabozantinib is 60 mg without food.

Treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery. Treatment should be withheld for grade 4 adverse reactions and for grade 3 or intolerable grade 2 adverse reactions that cannot be managed with dose reduction or supportive care. With return to baseline or resolution to grade 1, treatment should be resumed at a lower dose as follows: from 60 mg to 40 mg, and from 40 mg to 20 mg; in patients receiving 20 mg, treatment can be resumed at 20 mg if tolerated and otherwise discontinued.

In patients taking a strong CYP3A4 inducer (eg, rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine [Priftin], St John’s wort), the daily dose of cabozantinib should be increased by 20 mg (eg, from 60 mg to 80 mg or 40 mg to 60 mg), with resumption of the former dose 2 to 3 days after discontinuing the strong inducer.

Patients should not ingest foods (eg, grapefruit or grapefruit juice) or nutritional supplements known to inhibit cytochrome P450 during cabozantinib treatment.

Serious adverse events were reported in 40% of cabozantinib-treated patients, with the most common (≥ 2%) being abdominal pain, pleural effusion, diarrhea, and nausea. Doses were reduced in 60% of the cabozantinib group and 24% of the everolimus group; 20% of cabozantinib-treated patients had 20 mg/d as their lowest dose. The most common adverse events leading to dose reduction in cabozantinib recipients were diarrhea, palmar-plantar erythrodysesthesia syndrome, fatigue, and hypertension.

Adverse events led to treatment interruption in 70% vs 59% of the cabozantinib group and everolimus group, respectively, and to treatment discontinuation in 10% vs 10%. The most common causes in cabozantinib-treated patients were decreased appetite (2%) and fatigue (1%).

Report Adverse EventsHealth-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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